JoRussell-IDM
commented
4 years ago Ferreira 2004 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC524792/)
Dual origin of antigenic diversity -
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mutation and recombination -> allelic polymorphisms
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antigenic switching within clonotype
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ALLELIC POLYMORPHISM Most immune correlates of protection involve these polymorphic surface antigens (var, stevor, rifin, ama1, msp) where immunodominant small aa number repeat regions are a common theme
Most naturally acquired antibodies to msp1 recognize its variable domains, including those that have shown association with clinical immunity in humans
Moreover, cross-reactive epitopes on otherwise different repetitive antigens may prevent the affinity maturation of antibodies by causing an abnormally high proportion of mutated B cells to be preserved during clonal expansion
aa replacement in T cell epitopes in csp confrimed to be involved in immune evasion in naturally exposed people.
Cross-reactivity is a major factor driving the emergence and persistence of novel antigenic variants of malaria parasite antigens in human populations. High recombination rate found in repeats couples with positive selection of non cross reacting varaints accounts for most fo antigenic diversity in natural Pf populations.
mAbs can discriminate between variable repeat regions of dimorphic allele familes likes msp1/2 and these mAbs to MSP2 are putative associated with clinical immunity
polymorphism in the repetas might be implicated in the evasion of immune recognition from exposure of diverse forms of the same antigen. cross reactive epitopes on otherwise different repetitive antigens may prevent affinity maturation by causing abnormally high proportion of preserved B cell types during clonal expansion
pentapeptide VTEEI in several life stages of the parasite as example of this kind of broad cross reactive motif
the broad diversity of csp msp2 results primarily from indels from repeat motifs while msp1 seems to see a lot more exchanges of nonrepettive sequences and rearrangement within repeat arrays.
cross reactivity is a major factor driving emergence and persistence of novel antigenic variants with indels of repeat units within dimorphic alleliv families driving this immune recognition and evasion balance, evidence for narrowly specific abs to MSP1 block2 including Sowa paper describing an Ab that can discriminate only on copy number of hexapeptide SGGSVA
The balance between narrow and cross reactive Ab responses from acute to semi-immune infections.
clonal imprinting, evidence in kids in endemic settings Franks and Riley 2003 Infec. Immun.
- ANTIGENIC VARIATION
- RBCs an ideal hangout due to lack of MHC complec molecules Foreign antigen on the surface might play a complex role in keeping PMR low enough to not actually kill the host and to allow transmission to mosquito subtelomeric multigene families
young Pf trophs are in ciruclation in peripheral blood, nearly all late stage iRBCs and schizonts are sequestered in capillary vessels, avoiding splenic clearance
binding to endothelial receptors is causally associated with severe disease PfEMP1 proteins shown to bind to wide range of ERs as well as other molecules, proteoglycans and ABO antigens (see pathogenic basis for malaria in Doumbo 2002 Nature paper
Every Pf strain genome contains 40-60 var genes var genes seen in different strains are so variable - seemingly unlimited diversity, with some geographic structure
Mutually silencing transcription mechanism (Scherf Lanzer 1998 EMBO J, 103) silences all but one var gene per RBCs. switching occurs at a certain rate which may depend upon which var gene is initiall transcribed (Peters and Cheng 2002 PNAS, 84) Constant removal of RBCs expressing known PfEMP1 vars
Immunity to severe malaria is acquired after just 1-2 infections Number of different PfEMP1 subdomains (DBLa) recognized by African adults correlates inversely with probability of symptomatic malaria in next transmission season
Although pfemp1 is perhaps too broad for immunization, despite its central role in severe disease, motifs that bind to CD36 and CSA are structurally conserved, idela targets for inhibition of cytoadherence.
RIFINS are 200 genes wide per haploid Pf genome, althought they dont mediate cytoadhenerece, so they seem to have an unknown role (as of this pape) in virulence
Stevor are 30-40 per genome, much more conserved.
New alleles by ectopic recombination (Freitas-Junior and colleagues detected nonparental var genes in a genetci cross between Pf strains more frequently than the vailable extimates fo meiotic recombination. and chromosomal location of some parental alleles had changed in progeny . Ectopic recombination during mitosis, giving additional variation potential during chronic human infection and in vitro culture.
clinical immunity is due to gaps in variant specific antibody response
Ideal vaccine candidate might be an ancestral sequence wit the potential for inducing cross-protection against a wide range of antigenic variants (similar to HIV vaccinology, Gaschen Korber 2002 Science 46)
Gather observations from literature on how strains and antigen types within strains compete and are affected by immunity.
Should be some overlap with Philip's initial 1.0 mechanism for search in var gene space.
Should also be some valuable information in longitudinal parasitemiae (as in PRISM) for dominance by strain amidst complex infections.